Heart failure frequently occurs in patients with a normal ejection fraction (HFNEF) and affected subjects are predominately elderly, women with several co-morbid conditions. Despite the diversity of underlying clinical pathologies and co-morbid conditions present in these patients, a common pathophysiologic explanation is generally applied to explain their clinical symptoms, concentric hypertrophy leading to a small chamber size with decreased diastolic capacitance (decreased volume at a specific filling pressure). In such patients, the high resting left ventricular filling pressure is required for such hearts to maintain normal cardiac output. Our preliminary data revealed that although HFNEF is commonly thought of as being the result of a single hemodynamic mechanism, subgroups exist with distinctly different underlying pathophysiologies. Specifically, we documented that a significant subgroup with HFNEF have increases in ventricular volumes and expanded plasma volumes, consistent with a volume overload state. In the setting of a normal ejection fraction with end diastolic volume increased, stroke volume must increase, indicating a high output state. High output states involve peripheral (i.e.extra-cardiac) mechanisms, including anemia among others. Anemia may be an important, modifiable contributor to exercise intolerance in elderly HFNEF patients, abnormal ventricular remodeling and impaired overall health status and quality of life. Our pilot data suggests that the prevalence of anemia is high (> 50%) in elderly patients hospitalized with HFNEF, most of these subjects (76%) have a true anemia by blood volume analysis, which is associated with the glornerular filtration rate, suggesting that inadequate production of erythropoeitin may be a mechanism for their anemia. We have additionally, shown that anemic HFNEF subjects have poorer quality of life, more severe symptoms along with hemodynamic and structural cardiovascular changes compared with elderly subjects with HFNEF without anemia. Finally, preliminary data suggests that erythropoeitin adminstration to anemic HFNEF subjects results in improvements in submaximal and maximal exercise capacity. Concordant with our long-term goal to elucidate the pathophysiologic mechanisms that underlie the the syndrome of HFNEF and to develop effective therapies, we propose to evaluate the impact of treating anemia in elderly subjects with HFNEF. The specific aims of the current study are to provide a comprehensive and mechanistically based assessment of how correcting anemia in elderly subjects with HFNEF can impact on ventriuclar structure and funciton, functional capacity and overall health status. We propose to perform a randomized, prospective, double bind study in 120 elderly subjects with HFNEF to test the hypothesis that the administration of subcutaneous erythropoietin will be associated with significant reverse ventricular remodeling, increased exercise capacity and improved health status. Principle measurements will include six minute walk, maximal oxygen consumption and ventilatory anaerobic threshold by expired gas analysis; blood volume analysis, mesaures of renal function, health status by standardized questionnaires, and LV volumes, mass and function by three dimensional echocardiography. This study will examine the role of anemia in the pathophysiology of elderly patients with HFNEF and determine whether targeting anemia, one of many extra-cardiac factors that could contribute to the volume overload state that is characteristic of HFNEF, can ventricular remodeling and function, exercise capacity and health status. . [unreadable] [unreadable] [unreadable]